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Tenofovir Disoproxil Fumarate (Tenofovir DF) Versus Emtricitabine/Tenofovir DF in Subjects Resistant to Lamivudine

Primary Purpose

Hepatitis B

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

TDF

FTC/TDF

TDF Placebo

FTC/TDF Placebo

About this trial

This is an interventional treatment trial for Hepatitis B focused on measuring Tenofovir DF, Emtricitabine, Chronic hepatitis B, Combination therapy

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

Chronic HBV infection, defined as positive serum HBsAg for at least 6 months
18 through 75 years of age, inclusive
HBV DNA ≥ 10^3 IU/mL
Receiving treatment with lamivudine with confirmation of HBV reverse transcriptase mutation(s) known to confer resistance to lamivudine (rtM204I/V with or without rtL180M) by central laboratory assessment prior to randomization; adefovir dipivoxil treatment of ≤ 48 weeks at the time of screening (inclusive of combination adefovir dipivoxil + lamivudine at entry) was allowed
Willing and able to provide written informed consent
Negative serum pregnancy test (for females of childbearing potential only)
Calculated creatinine clearance ≥ 50 mL/min
Hemoglobin ≥ 10 g/dL
Neutrophils ≥ 1000 /mm^3
No prior oral HBV therapy with approved nucleotide and/or nucleoside therapy or other investigational agents for HBV infection other than lamivudine or adefovir dipivoxil

Exclusion Criteria

Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study
Males and females of reproductive potential who are not willing to use an effective method of contraception during the study
Alanine aminotransferase (ALT) ≥ 10 × the upper limit of the normal range (ULN)
Decompensated liver disease
Interferon or pegylated interferon therapy within 6 months of the screening visit
Alpha fetoprotein > 50 ng/mL
Evidence of hepatocellular carcinoma
Coinfection with hepatitis C virus, HIV, or hepatitis D virus
Significant renal, cardiovascular, pulmonary, or neurological disease
Received solid organ or bone marrow transplantation
Receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion
Proximal tubulopathy
Known hypersensitivity to the study drugs, the metabolites or formulation excipients

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Tenofovir DF

FTC/TDF

Arm Description

TDF plus placebo to match FTC/TDF

FTC/TDF plus placebo to match TDF

Outcomes

Primary Outcome Measures

Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

Secondary Outcome Measures

Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240

Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240

HBV DNA Level at Weeks 48, 96, 144, 192, and 240

Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240

Normal ALT was defined as having a value less than or equal to the ULN. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.

Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240

The percentage of participants who were HBeAg positive at baseline and who had HBeAg Loss at the given time point was summarized. Loss of HBeAg was defined as change of detectable HBeAg from positive to negative.

Percentage of Participants With Seroconversion to Antibody Against HBeAg (Anti-HBe) at Weeks 48, 96, 144, 192, and 240

The percentage of participants who were HBeAg positive at baseline and who had seroconversion to anti-HBe at the given time point was summarized. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative to positive.

Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Weeks 48, 96, 144, 192, and 240

The percentage of participants with HBsAg Loss at the given time point was summarized. Loss of HBsAg was defined as change of detectable HBsAg from positive to negative.

Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Weeks 48, 96, 144, 192, and 240

The percentage of participants with seroconversion to anti-HBs at the given time point was summarized. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative to positive.

Percentage of Participants With Virologic Breakthrough at Weeks 48, 96, 144, 192, and 240

The percentage of participants with virologic breakthrough at the given time point was summarized. Virologic breakthrough was defined as having two consecutive 1.0 log10 or greater increases in serum HBV DNA from on-treatment nadir, or two consecutive HBV DNA values ≥ 400 copies/mL after being < 400 copies/mL.

Percent Change From Baseline in Bone Mineral Density (BMD) of the Spine at Weeks 24, 48, 72, 96, 144, 192, and 240

BMD is calculated as grams per cubic centimeter (g/cm^2); the mean (SD) percentage change is presented.

Percent Change From Baseline in BMD of the Hip at Weeks 24, 48, 72, 96, 144, 192, and 240

BMD is calculated as g/cm^2; the mean (SD) percentage change is presented.

Development of Drug-resistant Mutations (DRMs)

The development of DRMs was summarized, either as development of new DRMs or enrichment of existing DRMs.

Full Information

NCT ID

NCT00737568

First Posted

August 15, 2008

Last Updated

February 9, 2016

Sponsor

Gilead Sciences

1. Study Identification

Unique Protocol Identification Number

NCT00737568

Brief Title

Tenofovir Disoproxil Fumarate (Tenofovir DF) Versus Emtricitabine/Tenofovir DF in Subjects Resistant to Lamivudine

Official Title

A Phase 3b, Randomized, Double-Blind, Double-Dummy Study Evaluating the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus Emtricitabine Plus Tenofovir DF Fixed-Dose Combination Therapy in Subjects With Chronic Hepatitis B Who Are Resistant to Lamivudine

Study Type

Interventional

2. Study Status

Record Verification Date

February 2016

Overall Recruitment Status

Completed

Study Start Date

September 2008 (undefined)

Primary Completion Date

November 2011 (Actual)

Study Completion Date

February 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Gilead Sciences

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The aim of therapy for the treatment of chronic hepatitis B virus (HBV) is to maintain suppression of viral replication to prevent the emergence of complications, which requires long-term therapy. Durable suppression of viral replication is achieved in the treatment of chronic viral diseases by preventing of the emergence of drug-resistant mutations. The clinical guidelines for the management of lamivudine resistant patients are variable. Some recommend switching to another agent without cross-resistance, while others recommend adding on another agent without cross-resistance. Limited clinical data exists to demonstrate whether tenofovir disoproxil fumarate (tenofovir DF; TDF) is an effective monotherapy for lamivudine resistant patients or if it should be used as part of a combination therapy regimen. This study is designed to evaluate the effectiveness, safety, and tolerability of tenofovir DF monotherapy versus emtricitabine (FTC)/tenofovir DF combination therapy in participants with chronic HBV with lamivudine resistance (presence of the rtM204I/V mutation with or without the rtL180M mutation) over a 240-week period. Participants in this study must be receiving lamivudine treatment at the time of enrollment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatitis B

Keywords

Tenofovir DF, Emtricitabine, Chronic hepatitis B, Combination therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

280 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Tenofovir DF

Arm Type

Experimental

Arm Description

TDF plus placebo to match FTC/TDF

Arm Title

FTC/TDF

Arm Type

Experimental

Arm Description

FTC/TDF plus placebo to match TDF

Intervention Type

Drug

Intervention Name(s)

TDF

Other Intervention Name(s)

Viread®

Intervention Description

Tenofovir disoproxil fumarate (tenofovir DF; TDF) 300 mg tablet administered orally once daily

Intervention Type

Drug

Intervention Name(s)

FTC/TDF

Other Intervention Name(s)

Truvada®

Intervention Description

Emtricitabine (FTC)/TDF 200/300 mg fixed-dose combination tablet administered orally once daily

Intervention Type

Drug

Intervention Name(s)

TDF Placebo

Intervention Description

TDF placebo tablet administered orally once daily

Intervention Type

Drug

Intervention Name(s)

FTC/TDF Placebo

Intervention Description

FTC/TDF placebo tablet administered orally once daily

Primary Outcome Measure Information:

Title

Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

Time Frame

Week 96

Secondary Outcome Measure Information:

Title

Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240

Time Frame

Weeks 48, 144, 192, and 240

Title

Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240

Time Frame

Weeks 48, 96, 144, 192, and 240

Title

HBV DNA Level at Weeks 48, 96, 144, 192, and 240

Time Frame

Weeks 48, 96, 144, 192, and 240

Title

Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240

Description

Normal ALT was defined as having a value less than or equal to the ULN. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.

Time Frame

Weeks 48, 96, 144, 192, and 240

Title

Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240

Description

Time Frame